A facile enantioselective synthesis of (S)-N-(5-chlorothiophene-2-sulfonyl) -β,β-diethylalaninol via proline-catalyzed asymmetric α-aminooxylation and α-amination of aldehyde

Article abstract of DOI:10.1016/j.tetlet.2010.10.029

A high-yielding enantioselective synthesis of the bioactive (S)-N-(5-chlorothiophene-2-sulfonyl)-β,βdiethylalaninol (1), a Notch-1-sparing γ-secretase inhibitor metabolite (with EC₅₀ = 28 nM) effective in reduction of Aβ production in vivo, has

Full text of DOI:10.1016/j.tetlet.2010.10.029

Tetrahedron Letters 51 (2010) 6565–6567
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Tetrahedron Letters
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A facile enantioselective synthesis of
(S)-N-(5-chlorothiophene-2-sulfonyl)-b,b-diethylalaninol via proline-catalyzed
asymmetric -aminooxylation and -amination of aldehyde
a
a
⇑
Varun Rawat, Pandurang V. Chouthaiwale, Vilas B. Chavan, Gurunath Suryavanshi, Arumugam Sudalai
Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A high-yielding enantioselective synthesis of the bioactive (S)-N-(5-chlorothiophene-2-sulfonyl)-b,b-
diethylalaninol (1), a Notch-1-sparing -secretase inhibitor metabolite (with EC50 = 28 nM) effective in
reduction of Ab production in vivo, has been realized starting from readily available 3-pentanone. The
key steps of the synthesis are proline-catalyzed -aminooxylation and -amination of aldehyde; the lat-
ter contributing an overall yield of 45.2% and 98% ee.
Received 31 August 2010
Revised 2 October 2010
Accepted 7 October 2010
Available online 14 October 2010
c
a
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
a
-Amination
Amino alcohol
-Aminooxylation
Proline
a
Alzheimer’s disease (AD) is a chronic, neurodegenerative disor-
der which is characterized by a loss of cognitive ability, severe
behavioral abnormalities, and ultimately death.1 A key event in
the pathogenesis of AD is now believed to be the deposition of b-
amyloid (Ab) plaques on the outside of the nerve cells in areas of
the brain that are produced by the proteolytic cleavage of amyloid
OH
HN
Cl
S
S
O
O
Figure 1. Compound 7.b.2 (1).
precursor protein (APP) by b and c
-secretase.2 A ‘b-amyloid cas-
cade’ hypothesis has emerged to account for various experimental
facts including genetic variations related to the production and
elimination of Ab.1a,3a Recent studies have further shown that neu-
ritic plaques and neurofibriliary tangles are accepted pathological
target.5 The synthetic sequence for 1, wherein proline-catalyzed
a-
aminooxylation9 and -amination10 reactions constitute key steps
a
for the introduction of chirality, is presented in Schemes 1 and 2.
Evidently, amino alcohol 9 has emerged as the key intermediate
in the synthesis of 1.
Thus, our synthesis of 1 commenced from 3-pentanone, which
on Horner–Wardworth–Emmons olefination (triethyl phosphono-
hallmarks of AD as confirmed at autopsy.3
c-Secretase inhibitors
like BMS-299897, LY-450139, and MK-0752 have entered clinical
trials.4,5 Recently (S)-N-(5-chlorothiophene-2-sulfonyl)-b,b-dieth-
ylalaninol 1 (7.b.2), a Notch-1-sparing c-secretase inhibitor (with
acetate, NaH, THF), gave the corresponding a, b-unsaturated ester
EC50 = 28 nM), has been found to be effective in reduction of Ab
production in vivo.5
2 in 93% yield. Hydrogenation [10% Pd/C, H2 (1 atm), MeOH] of the
unsaturated ester 2 produced the crude saturated ester, which was
directly subjected to reduction with LiAlH4 in THF at 25 °C afford-
ing the saturated primary alcohol 3 in 83% yield over two-steps.
Oxidation of primary alcohol 3 with IBX/DMSO mixture gave the
key precursor aldehyde 4, which was found to be highly volatile.
Hence, upon solvent extraction, it was immediately (without
Organocatalytic asymmetric synthesis has provided several new
methods for obtaining chiral compounds.6 In particular, proline, an
abundant, inexpensive amino acid available in both enantiomeric
forms has emerged arguably as the most practical and versatile
organocatalyst.7 In a continuation of our work on proline-catalyzed
synthesis of bioactive molecules,8 we wish to report a facile syn-
thesis of 1 (Fig. 1), whose activity makes it an attractive synthetic
purification) subjected to proline-catalyzed
and
-amination,10 respectively (Schemes 1 and 2).
Firstly, the -proline-catalyzed
-aminooxylation9 of aldehyde 4
a
-aminooxylation9
a
L
a
was carried out in a two-step reaction sequence: (i) reaction of
aldehyde 4 with nitrosobenzene as the oxygen source in the
⇑
Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.029

6566
V. Rawat et al. / Tetrahedron Letters 51 (2010) 6565–6567
i
ii
iii
O
OH
CHO
OH
CO2Et
vii
3
2
4
viii
iv
OTBS
OR'
N3
RO
H2N
5, R = R' = H
9
8
v
6, R = H ; R' = TBS
7, R = Ms ; R' = TBS
vi
Scheme 1. Synthesis of (S)-2-amino-3-ethylpentan-1-ol (9). Reagents and conditions: (i) triethyl phosphonoacetate, NaH, dry THF, 0–25 °C, 8 h, 93%; (ii) (a) H2 (1 atm), 10%
Pd/C, MeOH, 12 h, 25 °C; (b) LiAlH4, dry THF, 25 °C, 12 h, 83% (for two-steps); (iii) IBX, dry DMSO, 25 °C, 2 h; (iv) (a) PhNO,
L
-proline (20 mol %), CH3CN, ꢀ20 °C, 24 h then
MeOH, NaBH4; (b) H2 (1 atm), 10% Pd/C, MeOH, 12 h, 25 °C, 77% (over two-steps); (v) TBSCl, imid, CH2Cl2, 0–25 °C, 2 h, 81%; (vi) MsCl, Et3N, 45 min; (vii) NaN3, dry DMF, 60 °C,
30 h, 78% (for two-steps); (viii) LiAlH4, dry THF, 50 °C, 12 h, 75%.
alcohol 9 in 98% ee12 with an overall yield of 45.2%. The operation-
iii
i
ii
ally simple reactions with less number of steps, high overall yields
requiring a relatively low amount of inexpensive and non-toxic
proline as catalyst make this approach an attractive and useful
process.
1
Cbz
OH
OH
N
H2N
CHO
HN
Cbz
10
9
4
Scheme 2. Synthesis of 7.b.2 (1). Reagents and conditions: (i) dibenzyl azodicar-
boxylate, -proline (10 mol %), CH3CN, 0–20 °C, 3 h then MeOH, NaBH4, 92%; (ii) H2
(11.8 atm), Raney Ni, MeOH, AcOH, 70%; (iii) 5-chlorothiophene-2-sulfonyl chlo-
D
Acknowledgments
ride, Et3N, dry CH2Cl2, 0 °C, 30 min, 91%.
V.R. and P.V.C. thank CSIR, New Delhi for the award of fellow-
ships. The authors are also thankful to Dr. B. D. Kulkarni, Head,
Chemical Engineering and Process Development Division for his
encouragement and support.
presence of 20 mol %
treatment with NaBH4 in MeOH gave the crude
hol in situ and (ii) subsequent reduction of the crude
L
-proline in CH3CN at ꢀ20 °C followed by its
-aminooxy alco-
-aminooxy
a
a
alcohol with 10% Pd/C over H2 (1 atm) furnished chiral diol 5 in
77% yield over two-steps with 99% ee (determined from its Mosher
ester analysis). Selective protection of primary hydroxyl group in
diol 5 (TBSCl, imid, CH2Cl2) was achieved to produce the TBS ether
6 in 81% yield, followed by mesylation (MsCl, Et3N, CH2Cl2) of the
secondary alcohol which gave the corresponding mesylate 7. How-
ever, attempts to purify the mesylate via column chromatography
proved problematic due to its instability. This crude mesylate was,
therefore, treated immediately with sodium azide (DMF, 60 °C) to
References and notes
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afford the corresponding azide 8 in 78% yield {½a D25
ꢀ21.3 (c 1.6,
ꢁ
CHCl3)}. The LiAlH4 reduction of TBS azide 8 in THF at 50 °C affor-
ded the key intermediate (S)-2-amino-3-ethylpentan-1-ol 9 in 75%
yield with 99% ee, which was accomplished with the simultaneous
removal of TBS group (Scheme 1). Since the number of steps in-
volved in the
thereby limiting the overall yield (25.5%), we have explored alter-
native chemistry that involved a direct -amination approach.
Asymmetric -amination of aldehydes using proline as the cat-
alyst represents a burgeoning field of synthetic efforts toward syn-
thesizing chiral building blocks, such as -amino acids and
alcohols.10 Thus,
-amination of aldehyde 4 was carried out using
List’s protocol.10a Accordingly, aldehyde 4 was subjected to
-ami-
nation with dibenzyl azodicarboxylate in the presence of -proline
(10 mol %) to produce the -amino aldehyde, which upon in situ
a-aminooxylation process is relatively too many
a
a
a
a
a
D
a
reduction with NaBH4 afforded the protected amino alcohol 10 in
92% yield and 98% ee (determined by chiral HPLC). The amino alco-
hol 10 was then hydrogenated [Raney Ni, H2 (11.8 atm), MeOH,
AcOH (five drops)] to give (S)-2-amino-3-ethylpentan-1-ol 9 in
70% yield (Scheme 2).11 Finally, the amino alcohol 9 was condensed
with 5-chlorothiophene-2-sulfonyl chloride in the presence of Et3N
to afford the target molecule 1 in 91% yield and 98% ee (determined
by chiral HPLC)12 (Scheme 2).
6. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) List, B.; Seayad, J. Org.
Biomol. Chem. 2005, 3, 719; (d) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J.
2009, 15, 11058; (e) Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 6145.
7. For a review of proline-catalyzed asymmetric reactions see: List, B. Tetrahedron
2002, 58, 5573.
8. (a) Kotkar, S. P.; Sudalai, A. Tetrahedron: Asymmetry 2006, 17, 1738; (b) Kotkar,
S. P.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6813; (c) Narina, S. V.; Sudalai, A.
Tetrahedron Lett. 2006, 47, 6799; (d) Kotkar, S. P.; Chavan, V. B.; Sudalai, A. Org.
Lett. 2007, 9, 1001; (e) Chouthaiwale, P. V.; Kotkar, S. P.; Sudalai, A. ARKIVOC
2009, 88; (f) Rawat, V.; Chouthaiwale, P. V.; Suryavanshi, G.; Sudalai, A.
Tetrahedron: Asymmetry 2009, 20, 2173.
In conclusion, we have described a short synthetic route to 1
incorporating a successful application of
D-proline-catalyzed asym-
9. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293; (b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.;
metric -amination of aldehyde 4 to give the corresponding amino
a

V. Rawat et al. / Tetrahedron Letters 51 (2010) 6565–6567
6567
Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112; (d)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808; (e) Cordova, A.; Sunden, H.; Bogevig, A.; Johansson, M.; Himo, F.
Chem. Eur. J. 2004, 10, 3673.
CHCl3); 98% ee HPLC analysis: Column: ODH, mobile phase: hexane/isopropyl
alcohol (9/1), flow rate: 0.5 mL/min, retention time: 12.59 min (ꢀ)-isomer,
15.59 min (+)-isomer. IR (CHCl3, cmꢀ1): 3510, 3258, 2959, 2878, 1721, 1681,
1537, 1455, 1380, 1267; 1H NMR (200 MHz, CDCl3) d 0.69–0.87 (m, 6H), 1.26–
1.43 (m, 5H), 3.38–3.80 (m, 2H), 4.14–4.22 (m, 1H), 4.33 (br s, 1H), 5.12–5.27
(m, 4H), 6.39 (br s, 1H), 7.26–7.36 (m, 10H); 13C NMR (50 MHz, CDCl3): d 9.8,
10.1, 20.5, 21.3, 38.9, 60.4, 62.9, 68.2, 68.5, 127.8, 128.1, 128.3, 128.4, 128.5,
128.6, 135.1, 135.7, 157.3; Anal. Calcd for C23H30N2O5 requires C, 66.65; H,
7.30; N, 6.76; found C, 66.53; H, 7.10; N, 6.89%.
10. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (b) Bøgevig, A.; Kumaragurubaran,
N.; Juhl, K.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790;
(c) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J.
Am. Chem. Soc. 2002, 124, 6254; (d) Vogt, H.; Vanderheiden, S.; Brase, S. Chem.
Commun. 2003, 2448; (e) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am.
Chem. Soc. 2004, 126, 11770.
(S)-N-(5-Chlorothiophene-2-sulfonyl)-b,b-diethylalaninol
(1):
Colorless
11. Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103.
12. Spectral data of:
crystalline solid; mp 115–117 °C (crystallized from heptane:ethylacetate 4:1)
{lit.5b mp 115–117.6 °C}; ½a 2D5
ꢁ
+10.3 (c 0.3, MeOH) {lit.5b a 2D5
½ ꢁ +10.81 (1%
((S)-2-Azido-3-ethylpentyloxy)(tert-butyl)dimethylsilane (8): ½a D25
ꢁ
ꢀ21.3 (c 1.6,
solution, MeOH)}; 98% ee HPLC analysis: Column: ODH, mobile phase: hexane/
isopropyl alcohol (9/1), flow rate: 0.5 mL/min: retention time: 13.01 min (+)-
isomer, 13.56 min (ꢀ)-isomer). IR (CHCl3, cmꢀ1): 3519, 3301, 3068, 3034, 2957,
2881, 1615, 1456, 1337, 1130, 1090; 1H NMR (200 MHz, CDCl3) d 0.77–0.87 (m,
6H), 1.18–1.34 (m, 5H), 1.93 (br s, 1H), 3.31–3.42 (m, 1H), 3.57–3.60 (m, 2H),
4.93 (br s, 1H), 6.92 (d, J = 4.0 Hz, 1H), 7.42 (d, J = 4.0 Hz, 1H); 13C NMR
(50 MHz, CDCl3): d 11.4, 11.6, 22.7, 21.9, 42.8, 57.7, 62.6, 126.5, 131.5, 137.2,
140.1; Anal. Calcd for C11H18ClNO3S2 requires C, 42.37; H, 5.82; N, 4.49; found
C, 42.26; H, 5.76; N, 4.50%.
CHCl3); IR (CHCl3, cmꢀ1): 3064, 2896, 2110, 1600 1496, 1454, 1255, 1217, 967,
837; 1H NMR (200 MHz, CDCl3) d 0.08 (s, 6H), 0.84–0.92 (m, 15H), 1.33–1.37
(m, 5H), 3.40–3.45 (m, 1H), 3.64–3.77 (m, 2H); 13C NMR (50 MHz, CDCl3): d
ꢀ5.6, 11.2, 11.3, 18.2, 21.8, 22.5, 25.8, 41.8, 65.0, 66.2; Anal. Calcd for
C
13H29N3OSi requires C, 57.52; H, 10.77; N, 15.48; found C, 57.67; H, 10.83; N,
15.45%.
(S)-2-(1,2-Dibenzyloxycarbonylhydrazinyl)-3-ethylpentan-1-ol (10): Colorless
crystalline solid; mp 121 °C (crystallized from ethanol); ½a D25
ꢁ
+20.0 (c 1.0,